tbuckley/cabot-search huggingface dataset:
Comparison of efficacy and safety of neoadjuvant regimens for resectable esophageal squamous cell carcinoma: A meta-analysis.
Authors: Ting Wang, Liyu Cai, Zefeng Guo, Peimeng You, Shengbo Liu, Hongrui Qiu, Hao Li, Shaowei Wu, HaiYu Zhou
Journal: Journal of Clinical Oncology (2023)

e16098 Background: Recent studies have demonstrated that preoperative neoadjuvant therapy in esophageal carcinoma can bring extra survival benefits compared to surgical resection alone or postoperative adjuvant therapy. There is still a lack of high-level evidence from large randomized controlled clinical trials to define the interval between neoadjuvant therapy and surgery, radiotherapy dose and target area plans after neoadjuvant treatment, therefore we adopted a meta-analysis to compare the efficacy and safety of different neoadjuvant treatment options in esophageal squamous cell carcinoma (ESCC) in these clinical studies. Methods: Articles were retrieved from PubMed, Cochrane, Embase, Web of Science databases and abstracts of ASCO and ESMO meetings in 2021-2022 by the terms esophageal cancer, neoadjuvant therapy, Inclusion criteria: a: Patients with excisable stage esophageal cancer. Histopathological confirmed squamous carcinoma of the esophagus; b: At least one reported primary outcome as follows: pathological complete response (pCR) rate; major pathological response (MPR) rate. Statistical analysis was performed on Stata 16.0 and R 4.0 with a significance level of 0.05. Results: A total of 39 clinical studies with a total of 2,434 patients, mostly male, were included, with a predominance of phase 2 trials. 16 neoadjuvant chemotherapy combined with immunotherapy (nICT), 2 neoadjuvant immunotherapy alone, 5 neoadjuvant chemoradiotherapy combined with immunotherapy (nICRT), 15 neoadjuvant chemoradiotherapy (nCRT), 1 neoadjuvant chemotherapy, 32 single-arm studies, and 7 randomized controlled trials. The overall neoadjuvant therapy pCR rate was 36% (95% CI: 32%-40%) and the overall MPR rate was 55% (95% CI: 47%-63%). The nICT pathological complete response rate was 31% (95% CI: 26%-36%), nCRT pathological complete response rate was 38% (95% CI: 32%-44%) and nICRT complete pathological response rate was 49% (95% CI: 39% -59%). Complete pathological response rates were 36% (95% CI: 31%-41%) for neoadjuvant immunotherapy (with immunotherapy) and 33% (95% CI: 13%-54%) for neoadjuvant immunotherapy alone. 26 studies had a mean R0 resection rate of 93%, with the majority of patients achieving R0 resection. Conclusions: From this Meta-analysis it can be concluded that nICRT has the best complete pathological response rate of all neoadjuvant treatments and nCRT has a better complete pathological reponse rate than nICT, but most of them are not phase 3 clinical trials, therefore more studies are needed to further clarify the benefit of neoadjuvant radiotherapy combined with immunotherapy in esophageal squamous cell carcinoma.
Predictors of response in advanced colorectal cancer (CRC) patients treated with immune-checkpoint inhibitors (ICI).
Authors: Katherine K Benson, Samuel Paul, Eric Min, Menglin Xu, Anne M. Noonan, Arjun Mittra, Pannaga G. Malalur, Sameek Roychowdhury, Ning Jin, John L. Hays, Rifat T. Elkhatib, Shafia Rahman, Eric David Miller, Dayssy Alexandra Diaz Pardo, Ashish Manne
Journal: Journal of Clinical Oncology (2023)

e15579 Background: ICI is reserved for mismatch repair (MMR) deficient and high tumor mutation burden (TMB) CRC patients in the current clinical practice. Identifying clinicopathological factors predicting response to ICI beyond MMR status could help effectively utilize ICI in this population. This is a retrospective review of advanced CRC (recurrent or metastatic) patients treated with ICI at an academic institute to identify the risk factors (RF) for poor outcomes. Methods: CRC patients who received at least one dose of ICI for between 1/1/2015 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 46 advanced patients (37 colon and 7 rectal), the median age was 51 years (range 26-82) with 52% females, 95% Caucasians, 76% had metastatic disease (47% and 32% had liver and lung metastases or mets, respectively), 41% were mismatch repair (MMR) deficient, and 30% had KRAS exon two mutations. About 30% and 43% got ICI in the first line and ≥ 4 lines, respectively. Most patients received pembrolizumab (57%), followed by nivolumab (28%), atezolizumab (11%), and durvalumab (4%). Chemotherapy and ICI combination was given in 39%. irAEs were reported in 19% (n = 9). Median overall survival (OS) and progression-free survival (PFS) were 37 months (m) (95% confidence interval [CI], 14-NR) and 15m (95% CI, 7-35), respectively. Baseline (before the first ICI dose) albumin (p = 0.005), hemoglobin or Hb (p = 0.001), and the red cell count or RBC (p = 0.003) were negatively related to OS, while platelet to lymphocyte ratio or PLR (p = 0.01) and alkaline phosphatase levels (p = 0.03) were positively related to OS. High BL white cell count (WBC) (p = 0.04), alkaline phosphatase or ALP (p = 0.01), and low albumin (p = 0.002) and alanine transferase or ALT (p = 0.005) significantly impacted the OS. Other significant predictors are discussed in the table below. Conclusions: Our study provides insights into baseline tumor characteristics (such as lung/liver mets, KRAS exon 2 mutations, and MMR status) and lab values (such as RBC, Hb, PLR, albumin, ALP, and ALT) that could predict tumor response in CRC patients treated with ICI. These associations must be validated in larger studies. [Table: see text]
Ex-vivo analysis of programmed cell death on fibrolamellar carcinoma.
Authors: Olutani-Grace Ajay, Paul Kent, Robert Alan Nagourney, Tom Stockwell, Jessica Ellison, Susanne M. Swasey, Jordan C Tasse, Erik Schadde, Abhinav Humar, Tom Kato, Darrell Yamashiro
Journal: Journal of Clinical Oncology (2023)

4103 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with surgery as the only established treatment. Relapse is common (&gt;80%) and with 40% unresectable, there is a need for rationale systemic therapy. Empiric combinations, especially with lenvatinib (LEN) and gemcitabine (GEM), show promise, but are lacking a CLIA licensed laboratory rationale. Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD), from Nagourney Cancer Institute, is an attempt to meet this need. Methods: Nagourney Institute analyzed FLC tissue (as previously described), with a panel of 34 single/26 combinations of available/promising agents from 18 drug classes. Drug concentration with 50% cell death (LC50), below, within, or above 1-standard deviation of the mean (n ≥ 15), define Highly-Sensitive/Intermediate/Resistant, respectively. Active/Moderate/Inactive are similarly defined but with n &lt; 15. Actionable defines clinically available drug(s), not resistant/inactive and ≥ 6 assays. Results: Forty-four samples from 40 patients (17M,23F, age 6-56, 23 states/4 countries) were analyzed: 80% were viable and 69% of high quality for a total of 378 assays (avg 12/patient). However, all patients had actionable agents, and 78% of the assays showed activity in at least some patients. All the universally resistant/inactive assays (22%) were single agent. 76% of assays were actionable in at least one patient (100% for combinations compared to 62% for single agents). EVA-PCD replicate FLC studies and experience, such as the failure of monotherapy and the importance of LEN. Of 11 patients who had treatment that matched testing, 72% responded as predicted, including 6 with 100% response to LEN and/or QUE as predicted. Overall LEN/QUE, LEN/EVE, TRE, REG, QUE, 5FU/INF performed the best, while single agent ALP, CAB, LAR, VOR, GEM, DAS and IBR all showed 0% activity when tested &gt; 5 times. The largest challenge is the need for an adequate amount of viable tissue to arrive within 24 hours. However our experience demonstrates that it is feasible from other countries and across the US. Conclusions: This is the first demonstration of CLIA approved human FLC tumor testing. Data are in line with literature and correlates clinically. Prospective data are needed to fully incorporate EVA-PCD testing into the clinic. [Table: see text]
Genetic testing into survivorship after diagnosis of breast cancer.
Authors: Steven Katz, Rachel Hodan, Paul Abrahamse, Rachel Tocco, Timothy Hofer, Lauren P. Wallner, Allison W. Kurian
Journal: Journal of Clinical Oncology (2023)

10583 Background: Support for universal genetic testing after diagnosis of breast cancer is growing because of concerns that targeted guidelines fail to identify all patients who could benefit from genetic risk evaluation (GRE). Little is known about use of genetic testing in survivors of breast cancer over time. Methods: Women who were diagnosed with breast cancer in 2014-15 and reported to the SEER registries of Georgia and Los Angeles County completed a baseline survey about 9 months after diagnosis (N=2502). We performed a follow-up survey (FUPs) about 6 years after diagnosis among survivors (N=2347), of whom 1423 responded (60% response rate). We asked women about their receipt of clinical germline genetic testing and results, communication with relatives about cancer genetic testing, and use of direct-to-consumer testing (DTCt) after diagnosis. We categorized women into indications (yes/no) for GRE based on National Comprehensive Cancer Network guidelines at time of diagnosis (GRE indication baseline) and at the time of the follow-up survey (GRE indication FUPs only). Results: We present results for a preliminary sample (N=1272). About half of the respondents (44.6%) had indications for GRE over the study period; 28.0% at baseline; and an additional 16.6% at time of the follow-up survey (FUPs only). The Table below shows patient-reported testing at FUPs by GRE indication category (baseline, FUPs only, no indication). About two thirds of those with a baseline indication for GRE received genetic testing over the observation period: 66.5% vs 43.9% with indication at FUPs only vs 35.0% of those with no indication (p&lt;.001). A substantial proportion of those who reported testing received the test during the survivorship period (1 to 6 years post-diagnosis): approximately one-third of those with baseline indications vs over half of those with GRE indication at FUPs only. Testers with a pathogenic variant result (n=59) were much more likely to have talked to most or all of their first-degree adult relatives about genetic testing than those with a variant of unknown significance (n=40) or a negative finding (n=382): 64.3% vs 35.0% and 37.1%, respectively (p&lt;.001). Overall, there was very little interest in DTCt for cancer risk: 5.0% researched DTCt online somewhat to a lot; and only 3.5% had DTCt. Conclusions: The proportion of patients with indications for GRE after diagnosis of breast cancer markedly increases into survivorship but many patients do not receive genetic testing. Lack of survivor interest in DTCt for cancer risk is reassuring that patients are not substituting DTCt for clinical testing. [Table: see text]
The impact of household income on prostate cancer diagnosis, treatment, and outcomes.
Authors: John Panzone, Maximillian S Wu, Thenappan Chandrasekar, Alina Basnet, Gennady Bratslavsky, Hanan Goldberg
Journal: Journal of Clinical Oncology (2023)

5038 Background: Financial difficulties can lead to cancer patients delaying or deferring necessary care, resulting in later presentation with more advanced disease and worse clinical outcomes. Methods: A cross-sectional study was conducted assessing 488,853 prostate cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program between the years of 2010 and 2018. The association between annual household income (HHI) and diagnosis and outcomes of prostate cancer were examined using ANOVA and Chi-square analyses comparing clinical measures based on categorical HHI groupings. Results: Sociodemographic data and univariate analyses are displayed. The average age across all HHI classifications was 66.63 years. ANOVA analysis demonstrated that patients with a lower HHI had higher PSA levels upon diagnosis (12.10 vs. 10.90, 10.61, and 10.37 for &lt;=35k, 35-55k, 55-75k, and &gt;=75k, respectively, p&lt;0.001). Patients with lower HHI also demonstrated lower rates of undergoing surgical treatment (31.9%, 36.9%, 37.6%, and 35.1% for &lt;=35K, 35-55k, 55-75k, and &gt;=75k, respectively, p&lt;0.001) and the highest rate of disease metastasis to bone upon diagnosis (6.3%, 5.6%, 5.7%, and 5.8% for &lt;=35k, 35-55k, 55-75k, and &gt;=75k, respectively, p&lt;0.001). Lastly, patients with lower HHI demonstrated progressively higher rates of cancer-specific-mortality (8.4%, 6.8%, 6.5% and 5.1% for &lt;=35k, 35-55k, 55-75k, and &gt;=75k, respectively, p&lt;0.001), as well as higher overall mortality (21.2%, 18.0%, 15.0%, and 11.9% for &lt;=35k, 35-55k, 55-75k, and &gt;=75k, respectively, p&lt;0.001). Conclusions: In conclusion, these data suggest that prostate cancer patients with lower household income are diagnosed with more aggressive disease, tend to undergo surgery at lower rates, develop more advanced disease, and endure worse clinical outcomes than those in higher income brackets. Healthcare providers should be made aware of the clear associations between lower income and more aggressive disease at diagnosis, lower rates of surgical treatment and worse cancer-specific and overall mortality. [Table: see text]
TACE combined with the intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: A prospective, single-arm, phase II study.
Authors: Maoyuan Mu, Xiaobo Fu, Han Qi, Weiwei Jiang, Zixiong Chen, Fei Gao
Journal: Journal of Clinical Oncology (2023)

e16133 Background: Combination treatment with an immune checkpoint inhibitor and an anti-VEGF antibody is recommended as the standard care for advanced hepatocellular carcinoma (HCC). However, the efficacy of systemic therapy is less than satisfactory in BCLC stage C. Transarterial chemoembolization (TACE) combined with systemic therapy may synergistically improve patients’ clinical outcomes and obtain survival benefits. Intra-arterial infusion of Sintilimab and Bevacizumab has not been assessed previously. This study aimed to evaluate the safety and efficacy of TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab in patients with BCLC stage C HCC. Methods: This prospective, single-arm phase II study recruited 16 patients with advanced HCC. Main inclusion criteria: aged ≥ 18 years; a confirmed HCC (BCLC stage C) based on the ALSLD with either pathological or imaging findings; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7; ECOG performance status: 0-1. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Sintilimab (200mg, intra-arterial infusion, d1, Q3W) and Bevacizumab (7.5mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Sintilimab (200mg, intravenously, d1, Q3W) and Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1) and the secondary endpoints included disease control rate (DCR), time to progress (TTP), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: From September 2021 to December 2022, 16 patients with a median age of 52 years (range:38 -73) were enrolled. 12 (75%) patients with HBV infection and 6 (38%) with extrahepatic metastasis. 14 (88%) patients were classified as Child-Pugh A class. With a median follow-up of 5.4 months (range 3.9-14.3), the ORR was 63% (95%CI, 36.4%- 84.8%) with 3 CR and 7 PR per mRECIST v1.1, and the DCR was 69% (95%CI, 41.3%-89.0%). The median PFS was not reached. Adverse events in 31% of 16 patients were hypertension (3, 19%), fatigue (1, 6%), and proteinuria (1, 6%). The most common adverse event of grade 3 was hypertension (2, 13%). There were no treatment-related serious adverse events. Conclusions: TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab as the first-line strategy for advanced HCC patients (BCLC stage C) demonstrated a promising value by improving ORR, with acceptable side effects. Clinical trial information: NCT04796025 .
Tumor sensitization to PARP inhibitors by DNA damaging synthetically lethal acylfulvenes.
Authors: Aditya Kulkarni, Jianli Zhou, Kishor Bhatia, Panna Sharma
Journal: Journal of Clinical Oncology (2023)

e15123 Background: 20-30% of solid tumors (ovarian, breast, pancreatic, prostate cancers) harbor some level of deficiency in DNA Damage Repair (DDR) pathways. Such cancers become dependent on alternative DDR pathways to maintain genome integrity, making them selectively vulnerable to DNA damaging agents. The concept of synthetic lethality has been leveraged to treat subsets of such tumors. Clinically, PARP inhibitors (PARPi) have been successful in Homologous Recombination Deficiency (HRD) cancers. LP-100 and LP-184 are acylfulvene (AF) class small molecule prodrugs that are metabolized to active compounds by prostaglandin reductase 1 (PTGR1) that is often elevated in solid tumors. AF-induced DNA lesions are likely selectively processed by repair pathways including BRCA1/2 mediated Homologous Recombination (HR). Methods: Cell Titer Glo based 10 day cell viability assays were used to generate drug IC50 values in vitro. Bliss synergy scores were computed with scores ≥ 10 reflecting synergy. Drug-induced DNA double strand breaks (DSB) were detected and quantified with STRIDE (SensiTive Recognition of Individual DNA Ends) assay in cancer cells. A subcutaneous tumor xenograft model was used to determine tumor volumes in control and drug treated mice. Results: In a BRCA2 mutant ovarian cancer cell line OVCAR3, LP-184 and olaparib co-treatment in vitro showed synergistic effects (Bliss score 10). Similarly in a BRCA2 mutant prostate cancer cell line 22Rv1, LP-100 combination with rucaparib was synergistic (Bliss score 18). 400 nM LP-184 showed a time dependent increase in DNA DSB signals in vitro, 1.7X more so in BRCA2 mutant vs wild type (WT) DLD-1 isogenic colon cancer cell lines up to 24 hours. To validate the hypothesis that AF-induced DSBs remain unresolved if exposed to and further synergize with PARPi in vivo, we tested LP-100 plus olaparib in a DU145 (BRCA2 mutant) prostate cancer xenograft model. LP-100 + olaparib treatment resulted in sustained, durable tumor regression indicating in vivo synergy whereas either agent alone did not produce tumor shrinkage. Day 42 tumor growth inhibition was 66% for 2.5 mg/kg LP-100 alone, 34% for 40 mg/kg olaparib alone and 108% for the combination. Moreover, LP-184 treatment resulted in early onset and complete tumor regression in 7 PDX models of PARPi resistant triple negative breast cancers (TNBC) harboring BRCA1/2 loss whereas olaparib/ niraparib remained entirely ineffective in these. Conclusions: AF response is influenced by tumor DNA repair competence. LP-100 and LP-184 are synthetically lethal resulting from their abilities to cause unresolvable DNA damage where tumor cells express high PTGR1 and are deficient in the HR pathway. LP-184 single agent was superior to PARPi in TNBC and LP-100 combination made an olaparib resistant tumor highly sensitive, thereby facilitating a path to extend the opportunities for both AFs and PARPis and enhance the clinical utilization of PARPi.
A novel <sup>89</sup>Zr-a-PD-1 immuno-PET-CT may improve pseudoprogression detection in a lung cancer murine model receiving immunotherapy.
Authors: Ander Puyalto Calvo, María Rodríguez-Remírez, Ines Lopez, Fabiola Iribarren, Maria Torregrosa, Jon Ander Simon, Marga Ecay, Maria Collantes, Anna Vilalta, Alejandro Francisco-Cruz, Jose Luis Solorzano, Ivan Peñuelas, Daniel Ajona, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2023)

e15116 Background: Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment improving survival outcomes of non-small cell lung cancer (NSCLC) patients. Response assessment of patients on ICIs treatment represents a challenge since an increase in tumor size or the appearance of new lesions might not reflect true disease progression (P) but pseudoprogression (PP), which has been reported in a range of 3-6% in NSCLC. Conventional 18 F-FDG-PET scans do not accurately discriminate P from PP. We have recently reported the efficacy of a combined blockade of PD-1 and ID1 in NSCLC mouse model. We aimed to evaluate a novel 89 Zr-labelled radiotracer for micro mPET-CT to detect PP in a NSCLC murine model. Methods: Syngeneic subcutaneous tumors were generated using LLC cells (with constitutive expression of ID1 or ID1-silenced) in C57BL6J and in ID1-deficient mice, treated with PBS or with a commercially available monoclonal antibody against PD-1 (a-PD-1) (RPM1-14, 300 mg, IP, on days 7, 10 and 14). Tumor growth and response to ID1-PD-1 blockade, was measured by 18 F-FDG uptake. Additionally, PP was measured labelling the anti-PD-1 with 89 Zr ( 89 Zr-a-PD-1) and analyzing 89 Zr uptake at day 15, 17 and 20. Tumor microenvironment was analyzed with immunohistochemistry, multiplex immunofluorescence and quantification of relative expression of interleukins by RT-PCR. Results: 18 F-FDG uptake did not show significant differences between groups, underestimating the real metabolic response induced by the treatment. However, 89 Zr-mPET-CT showed a significantly higher 89 Zr uptake when ID1 was inhibited in both, tumor cells and tumor micro-environment and mice were treated with a-PD-1 (p = 0.0075). The analysis of the tumor tissues in those animals by immunohistochemistry and multiplex immunofluorescence disclosed an increase in immune T CD8 + cells infiltration, being responsible for the antitumor response observed and correlating with 89 Zr signal. Moreover, the analysis of interleukins expression showed that tumors with ID1 inhibition in the tumor micro-environment presented an upregulation of pro-inflammatory interleukins, favoring T- cell infiltration. Conclusions: ID1 inhibition in tumor cells and in tumor micro-environment combined with PD-1 blockade enhanced immune cell infiltration through pro-inflammatory interleukins upregulation. 89 Zr-a-PD-1 immuno-PET-CT may improve PP detection in a NSCLC murine model receiving immunotherapy.